Severe cutaneous necrosis in antiphospholipid syndrome
Authors: Mariam Mostafa, Amir Mahmoud, Hebat‐Allah Egiza, Chengu Niu, Mohamed Elbahnasawy, Yasmin Yusuf, Peter Kouides
Journal: American Journal of Hematology (2023)

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent thrombosis and/or recurrent fetal loss. APS can be primary or secondary to autoimmune disorders such as systemic lupus erythematosus (SLE). It is unique from other thrombophilic disorders in that it predisposes patients to not only venous but also arterial thrombosis through endothelial cell damage and activation of platelets.1 The Sydney Criteria are used for diagnosis of APS and necessitate the presence of one clinical and one laboratory criteria.2 Clinical criteria consist of objectively confirmed venous, arterial or small vessel thrombosis, or pregnancy complications that may be attributed to placental insufficiency, including pre-eclampsia, pregnancy loss, or premature birth. Laboratory criteria consist of a positive laboratory test (lupus anticoagulant, anticardiolipin anticoagulant and/or anti-B2 glycoprotein) found on 2 or more occasions at least 12 weeks apart.2 Management of APS involves the long-term use of vitamin K antagonists. Catastrophic APS (CAPS), as the name implies, is a disastrous complication of APS. The International Congress on aPL has proposed criteria for diagnosis of CAPS; Definite CAPS requires all four of the following criteria: involvement of three or more organs, systems or tissues, manifestations develop simultaneously or in less than 1 week, small vessel occlusion that is confirmed histologically in at least one organ or tissue and presence of antiphospholipid antibodies twice at least 12 weeks apart. Probable CAPS diagnosis requires less stringent criteria (involvement of only two organs or sites of tissue involvement and manifestations of a third event develops between 1 week and 1 month after presentation despite anticoagulation).3 Although CAPS only occurs in less than 1% of patients with APS, when present, it is associated with high morbidity and mortality with the majority of patients requiring ICU admission for multi-organ failure.4 Cutaneous manifestations are recognized in the clinical spectrum of APS and include ulcers, pseudovasculitic skin lesions and digital gangrene.5 Less commonly reported is cutaneous skin necrosis, for which there have only been 14 case reports since the year 2000. We now present a rare case of APS with cutaneous necrosis and summarize clinical presentation and management of previous cases reported in the literature since the year 2000. A 36-year-old obese female patient with past medical history of hypertension, tobacco use, peripheral neuropathy, peripheral vascular disease with previous stents, and APS presented with worsening left lower extremity and perennial wounds. One year prior, she had been given a diagnosis of primary APS when she presented with a small ulcer on her left foot and laboratory testing revealed positive lupus anticoagulant, high titers for anticardiolipin immunoglobulin G (ACL IgG) (>150/mL) and B2-glycoprotein IgG (B2GP IgG) (>150 U/mL). Skin biopsy from the patient's initial presentation at the time with a skin ulcer on her toe revealed thrombotic microangiopathy and she was placed on warfarin (see Figure 1). She then presented 10 months later with a perineal wound and gangrenous toes. This occurred despite being on warfarin with average INR before admission 1.9. She required multiple amputations to all her left toes and surgical debridement leaving a poorly healing lateral wound on the left foot that failed skin graft. She presented to our institution with worsening cutaneous necrosis on the left foot stump, thigh, perineal decubitus ulcer, and fever (Figure 1). Labs revealed microcytic anemia (hemoglobin 6.8 g/dL, mean corpuscular volume 76 fl), thrombocytopenia 81 × 103/μL, and elevated inflammatory markers (erythrocyte sedimentation rate 102 mm/h [normal 0–30 mm/h], C-reactive protein 240 mg/L [normal 0–10 mg/L]). Coagulation profile was significant for PT of 21.6 s (normal 10.2–12.9 s), INR 1.9, PTT 100 s (normal 25.1–36.5 s), and fibrinogen 978. She was also triple positive with positive lupus anticoagulant, ACL IgG titer of 112 U/mL (negative < 20 U/mL) and B2-glycoprotein IgG titer >150 U/mL (negative < 15 U/mL). She had a negative thrombophilia gene workup including factor V Leiden and prothrombin gene mutation. She had polymicrobial growth from her wound culture and her blood cultures were negative. There was no evidence of deep venous thrombosis or osteomyelitis by ultrasound and bone scan respectively. The patient did not have any other organ affection and therefore she did not meet criteria for CAPS. Her warfarin was initially transitioned to low molecular weight heparin in response to her thrombocytopenia. Subsequently, anticoagulation was interrupted briefly as platelet count continued to drop to a nadir of 24 × 103/μL but she continued on half dose LMWH while platelet count was between 25 and 50 × 103/μL and with full dose anticoagulation once her platelet count recovered to >50 × 103/μL. Her rapidly worsening cutaneous necrosis and thrombocytopenia were thought to be a manifestation of severe anti-phospholipid syndrome (though not meeting CAPS criteria) with immune mediated thrombocytopenic flare (as opposed to disseminated intravascular coagulation given elevated fibrinogen without worsening in PT and INR). She was started on aggressive therapy with a quadruple regimen of intravenous immunoglobulin (IVIG), high dose steroids, plasma exchange and rituximab. IVIg infusion was given Day 1 and Day 7 (1 g/kg), methylprednisolone was given on Day 1–3 (500 mg/day), rituximab was given on Day 7 and Day 21 (1 g), and daily plasma exchange was started from Day 1 up to and including Day 7 (Figure 1 shows platelet count trends and timing of therapy). Her platelet count normalized on Day 15, and a heparin infusion was started on Day 3 once platelet counts reached 50 × 103/μL. The patient underwent left below knee amputation and surgical debridement without complications. She was transitioned back to warfarin with a higher INR goal (2.5–3.5). Antiplatelets with aspirin was initiated after the amputation once platelet count recovered. She continued to have stable platelet count and post-operative healing of her wounds (Figure 1). Cutaneous necrosis is a rare presentation of APS. Our case presented with cutaneous necrosis in her left foot, thigh and perineum along with severe thrombocytopenia. She was managed aggressively with IVIg, high dose steroids, plasma exchange and rituximab and required a below knee amputation and cutaneous tissue debridement. Her platelet counts stabilized and the cutaneous lesions resolved with treatment. There are no established standards of care for management of cutaneous necrosis in APS patients with only a few case reports documenting case presentations and management since 20006-16 (with all cases detailed in Supporting Information S1). Table 1 summarizes the characteristics of APS patients who developed cutaneous necrosis in previous case reports since the year 2000. The average age of patients presenting with cutaneous necrosis was 45 years (with median age of 46 years). The majority of patients were female (86.6%) and had primary APS (60.0%). A third of the cases also presented with CAPS. A prospective cohort study by Cervera et al. of 1000 patients with APS showed that the mean age was 34 years with a female to male ratio of 5:1 (83.3% female) similar to that reported for APS patients in a large cohort study.5 That cohort also reported that 53% of APS patients had primary APS and 36% of patients had secondary APS associated with SLE similar to our study. However, Cervera et al.'s cohort only showed 0.8% of patients with CAPS compared to the 33.3% of patients reported here, which suggests that cutaneous necrosis may be a manifestation that accompanies a more severe form of APS that is more likely to be associated with CAPS. The authors of the cohort went on to describe cutaneous manifestations and reported that ulcers occurred in 4% of patients, pseudovasvulitic skin lesions occurred in 2.6% and digital gangrene occurred in 2% with cutaneous necrosis not specifically mentioned. Given that warfarin is the drug of choice for treatment of APS, an important differential to consider in patients presenting with necrosis is warfarin-induced skin necrosis (WISN). It can be differentiated from cutaneous necrosis in that WISN usually appears temporally within 1 week of initiating warfarin and that it tends to cause deep tissue necrosis unlike APS cutaneous necrosis which is usually superficial.17 On biopsy, cutaneous necrosis in APS syndrome appears as thrombosis of dermal capillaries without features of vasculitis.17 Another study by Cervera et al., which gathered data from an international registry of 280 patients with CAPS showed that mean age was 37 years and similar to APS the majority of patients were female (72%). In that study, 46% of patients with CAPS had primary APLS, 40% had secondary APS associated with SLE, 5% had secondary APS associated with SLE-like disease, and 9% had secondary APS associated with other autoimmune diseases.4 While our patient did not develop full-blown CAPS, a third of the case reports discussed in this review did indeed have CAPS. While CAPS is a rare phenomenon occurring in only 1% of APS patients, it is associated with high morbidity and mortality (44% mortality in Cervera et al.'s study) with the majority of patients requiring ICU admission for multi-organ failure.4 Therefore, given the relatively high frequency of CAPS in APS patients with cutaneous necrosis, it is important that clinicians have a heightened surveillance for it to allow for early diagnosis and management. The pathophysiology behind cutaneous necrosis in APS has not been well studied, but appears to be driven by similar principles of widespread small vessel thrombosis and a component of reactive inflammation. Multiple mechanisms have been postulated for effect of antiphospholipid antibodies mediate thrombogenesis including monocyte and endothelial cell activation, modulation of protein C and antithrombin, disruption of annexin A5, complement activation, and mTOR activation.18-21 Moreover, a two-hit hypothesis exists that suggests a role for an underlying vascular or inflammatory injury predisposing to thrombosis by antiphospholipid antibodies.22 These precipitating factors have been generally identified more often in patients with CAPS, likely explaining the higher frequency of cutaneous necrosis in patients with CAPS or more severe APS. Based on our aggregated literature review of similar cases, patients were treated with anticoagulation (100%), steroids (86.6%), plasma exchange (40.0%), rituximab (33.3%), IvIg (20.0%), and anti-platelet agents (26.6%). Other immunosuppressive agents were used in some cases (azathioprine, mycophenolate mofetil, cyclophosphamide, hydroxychloroquine) with further details of treatment available in Table 1 and Supporting Information S1. The majority of patients also required surgery at some point in their acute presentation (60.0%). There is no established approach to managing cutaneous necrosis in APS. The severity of the diagnosis, high morbidity (60.0% of patients required surgery for debridement or amputation), and high association with CAPS suggests that a treatment algorithm similar to that of CAPS may be prudent. In Cervera et al.'s registry of CAPS patients, patients were commonly managed with anticoagulants (87%), steroids (86%), plasma exchange (39%), cyclophosphamide (36%), and IVIg (22%). The study showed that the highest recovery rate was achieved in patients managed with combination of anticoagulants, corticosteroids plus plasma exchange and/or IVIG (69% vs. 54%), although this observation did not reach statistical significance (p = .089).4 Anticoagulation is the cornerstone in treatment for patients with APS including those with cutaneous necrosis. Oral vitamin K antagonists are the standard of care for oral anticoagulation with goal INR 2–3. The strategy to treat to higher INR target of 3–4 has not been shown in randomized controlled trials to provide increased benefit compared to INR target 2–3.23, 24 However, these studies did not take into consideration risk factors such as previous arterial thromboses, recurrent thromboses while on anticoagulation, and presence of triple positive antibodies, which are associated with higher risk of thrombosis and require dedicated study on benefit of higher INR target.25 The use of antiplatelet therapy in patients with APS has been utilized in patients with arterial thrombosis. The combination of antiplatelet therapy with vitamin K antagonists in patients with APS with history of arterial thrombosis has been shown to decrease recurrent thrombosis.26 In the setting of thrombocytopenia, there is a dearth of studies on APS patients but studies on acute coronary syndrome patients recommend holding antiplatelet therapy if platelet count is <50 × 103/μL due to high risk of bleeding.27 Rituximab is also used in APS because it causes B cell depletion, which reduces levels of cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, IL-2, and IL-6, which mediate some of the pathology observed in CAPS.28 However, rituximab does not affect memory B cells and while it does cause clinical improvement in manifestations of APS including leg ulcers, rituximab use does not decrease APL antibodies.29, 30 The guidelines on apheresis also recommend that for patients with CAPS a triple to quadruple therapy approach be used which employs anticoagulation, steroids and plasma exchange and/or IVIg. The authors of the guideline postulate that the therapeutic benefit of plasma exchange in CAPS patients may be due to removal of antiphospholipid antibodies, cytokines, tumor necrosis factor alpha and complements and it is reasonable to assume the same benefits would apply for patients with cutaneous necrosis. The apheresis guidelines also recommend based on expert opinion that plasma (with or without albumin) be used as replacement fluid to allow for repletion of antithrombin III (the main site of action of heparin) and other natural anticoagulants like protein C and S. They further recommend daily or every other day plasma exchange for at least 3–5 days with possibility of extending for longer courses as clinically indicated.31 Plasma exchange has been associated with a transient decrease in coagulation factors, antithrombin III, and protein C and S when plasma is not used as a replacement fluid.32 However, it has also been associated with decreased anti-Xa activity which interferes with the action of anticoagulation33 but overall, studies show increased risk of bleeding.34 Interestingly, in our review of cutaneous necrosis cases and of apheresis guidelines cited above, use of a C5 inhibitor (eculizumab, ravulizumab) was not reported but there are emerging case reports of C5 inhibitor therapy in CAPS.35 The role of eculizumab in CAPS is still under investigation with current use being limited to case reports. Previous authors have analyzed complement activity but not complement gene mutations before employing eculizumab in CAPS patients.36 There is also a role for mTOR inhibitors such as sirolimus in management of APS and CAPS given the role of mTOR activation in thromboinflammation in APS but further studies are needed to delineate their clinical role in such a setting. Use of sirolimus in APL-positive kidney transplant recipients was associated with preservation of kidney function, compared with patients on other immunosuppressive therapy.21 There are also guidelines by the Japanese Dermatological Association that focus on local management of connective tissue disease/vasculitis-associated skin ulcers.37 While cutaneous necrosis does not exactly fall into that category, their recommendations may aid in wound management. They recommend antibiotics as needed for infection, local wound care using cadexomer iodine ointment to eliminate necrotic tissue and allow for local control of infection. For moist wounds, the authors recommend trafermin spray, PGE1 ointment, and for dry wounds tretinoin tocopherol ointment. The authors of the guidelines caution against covering the ulcers with dressing as rapid deterioration can frequently occur and may be missed/caught late due to time interval between dressing changes. Regarding surgery, the guidelines posit that the decision should be considered thoughtfully with preference toward conservation as ulcers and wounds related to connective tissue diseases can often heal by treating the primary condition, and careful management can save tissue. They recommend that if the tissue is frankly necrotic, it should be removed but attention should be taken to preserve the ischemic basement tissue if possible. Skin grafting should be considered when possible. Medical management recommendations that they provide for APS patients include giving anticoagulation with antiplatelets being reserved for high-risk patients with recurrent thrombosis despite treatment with anticoagulation and plasma exchange.37 In the patients we summarized here, 60% required surgery varying from debridement to amputation with two patients undergoing skin grafts successfully. Cutaneous necrosis is a rare complication of APS. Our case presentation along with literature review summarizes such cases reported in the literature along with their management and outcomes. While all the cases reported had resolution of their cutaneous lesions and there were no deaths, our review is based on existing case reports, which are biased toward patients with good outcomes, as patients who had negative outcomes are less likely to be reported upon and/or published. Further studies are needed to more clearly delineate optimal management of this serious manifestation of APS. All authors contributed to writing and editing of manuscript. We would like to acknowledge Azza Mohamed for her support with the manuscript. No funding to declare. The authors declare no conflicts of interest. Data available on request from the authors. Data S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.